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Stem cells: A Closer Look

iPSCs allow a unique examination of how bipolar disorder develops, affects the brain, and may be more successfully treated.

Primitive neurons (indicated in red) developed from induced pluripotent stem cells in the bipolar disorder research at U-M

In recent years, you’ve probably heard a lot about the promise of using “stem cells” for everything from studying diseases in the lab to treating injury and illness in the clinic. So what exactly are stem cells, and how are they being used at U-M to learn more about the origins, progression, and treatment of bipolar disorder?

Stem cells are different from other types of cells in the body because they have the ability to develop into many different varieties of specialized cells (such as blood cells or muscle cells), and they can also replenish themselves indefinitely. The ability to “self-renew” means that an infinite supply of this valuable living material is available for research; for medicine, it means that stem cells may offer a potentially limitless source of replacement cells and tissues (perhaps even organs for transplantation) to treat a wide variety of illnesses, conditions, and disabilities.

Stem cells can come from several sources in the human body. For years, stem cells taken from embryos just a few days after fertilization that were no longer needed for family building seemed to offer the greatest potential for applications in research and medicine because of their extraordinary flexibility and their capacity to develop into nearly any type of cell in the body.

More recently, researchers have found a way to “reprogram” regular adult cells to endow them with the same valuable properties offered by embryonic stem cells, while sidestepping their sometimes tricky ethical issues. These cells are known as “induced pluripotent stem cells,” or iPSCs.

In a project launched by the Prechter Bipolar Research Program at the Depression Center, researchers are developing iPSCs from ordinary skin cells, contributed by people with and without bipolar disorder. First the skin cells are coaxed to behave like embryo-derived cells, and then developed to neurons from the brain. Through this transformation process, the researchers can examine how the cells that originated from people with bipolar form and react to stress and medications compared to the cells donated from people without the condition.

Since the skin cell donors are also participants in the Prechter Longitudinal Study of Bipolar Disorder, the study team can make connections between years’ worth of extraordinarily rich data from these individuals and information obtained from studying the newly formed neurons in the lab.

The project’s overall goal is to develop a richer understanding of the biological and genetic basis of bipolar disorder, including why people may respond differently to specific treatments or exposure to stressors. So far, it appears that the neurons developed from people with bipolar have elevated levels of genes that form membrane receptors; this may affect how neurons react to stimuli. The research team is currently investigating the implications of this finding for cell functioning and behavior, and by extension what that could mean for people who live with the disorder, with the goal of identifying new treatments.

The project is supported by the Steven M. Schwartzberg Memorial Fund.

According to Sue O’Shea, Ph.D., who co-directs U-M’s A. Alfred Taubman Consortium for Stem Cell Therapies core laboratory, where the iPSCs are developed, being able to study bipolar disorder using what essentially amounts to a ‘brain in a dish’ offers many advantages over examining brain tissue donated by individuals after their death (and of course, accessing living brain tissue in humans for study is impossible for ethical and other reasons!).

Since scientists have not identified a central area of the brain involved in bipolar disorder (instead, the disease has been associated with diffuse changes to several areas), it makes it nearly impossible to know what type of brain cell, or region of the brain to study. The ability to develop a brain cell representing an earlier, more primitive life stage should allow the research team to determine precisely when and how a disease like bipolar disorder may develop in the brain.

O’Shea and her team believe that in the long term, iPSCs will be very important for personalized medicine and the ability to optimally match treatments to individuals. One potential application of iPSCs could be to determine how an individual might respond to treatments by first modeling the conditions in the lab, essentially by looking at how that person’s cells respond to different medications, different doses, or combinations of drugs.

In the same way that stem cells are becoming more widely used to regenerate damaged or diseased tissue in various organs and body systems, could this technology one day be used to treat brain illnesses? It’s not outside the realm of possibility. Several U-M researchers are investigating whether cells transplanted into the central nervous system of rodents may integrate and connect with other neurons and whether that affects their behavior, and others are also involved in a clinical trial treating spinal cord disease in humans using stem cells. Although there is still much to learn about these complex cells, they hold the potential to dramatically transform our understanding of neuropsychiatric disorders and their treatment.